Thiamine diphosphate analog 1, an analog of Thiamine diphosphate (the active form of vitamin B1 and a universal cofactor in key cellular pathways), mirrors the structure and potentially the function of its prototype.
NHC-diphosphate is an active phosphorylated intracellular metabolite of β-d-N4-Hydroxycytidine (NHC) as a diphosphate form[1]. NHC is a pyrimidine ribonucleoside and behaves as a potent anti-virus agent. NHC effectively inhibits the replication of venezuelan equine encephalitis virus (VEEV), Chikungunya virus (CHIKV) and hepatitis C virus (HCV)[1]. Huh-7 cells are incubated with (10-50 μM; 4 h) NHC or a McGuigan phosphoramidate prodrug of NHC.Intracellular levels of the parental compounds and phosphorylated metabolites are measured using LC-MS MS. Small amounts of NHC-monophosphate (MP) and NHC-diphosphate can be observed, while NHC-triphosphate remains the most abundant metabolite.[1].
NHC-triphosphate triammonium is an active phosphorylated intracellular metabolite of β-d-N4-Hydroxycytidine (NHC) as a triphosphate form[1]. NHC-triphosphate triammonium is a weak alternative substrate for the viral polymerase and can be incorporated into HCV replicon RNA[1][2]. In an intracellular metabolism assay, HCV replicon cells are treated with 10 μM 3H-labeled NHC, and intracellular nucleotide levels are determined after 1, 2 and 8 hours incubations. NHC is rapidly convered into the mono-, di-, and triphosphate forms, and NHC-TP reaches up to 71.12 pM after 8 hours[1].NHC-triphosphate triammonium (NHC-TP) (5-40 μM) absence leads to full-length polymerization products, it can be a weak alternative substrate. In addition, incorporation of NHC-TP instead of CTP increases the molecular weight of the polymerization product by 16 (one extra oxygen) for each event and an obvious electrophoretic shift is observed in cell-free HCV NS5B polymerization reactions[1].Huh-7 cells are incubated with (10-50 μM; 4 h) NHC or a McGuigan phosphoramidate prodrug of NHC. Intracellular levels of the parental compounds and phosphorylated metabolites are measured using LC-MS MS. Small amounts of NHC-monophosphate (MP) and NHC-diphosphate (DP) can be observed, while NHC-triphosphate triammonium remains the most abundant metabolite[2].NHC-triphosphate triammonium (NHC-TP) metabolite may directly target the viral polymerase and behave as a nonobligate chain terminator. It plays a prominent role in inhibiting early negative-strand RNA synthesis, either through chain termination or mutagenesis, which may in turn interfere with correct replicase complex formation. [1]. Stuyver LJ,et al. Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses in culture.Antimicrob Agents Chemother. 2003 Jan;47(1):244-54. [2]. Maryam Ehteshami, et al. Characterization of β-d- N4-Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus.
Ins(1,2)P2 (sodium salt) is one of the many inositol phosphate (InsP) isomers that could act as small, soluble second messengers in the transmission of cellular signals. The most studied InsP Ins(1,4,5)P3, is a second messenger produced in cells by phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol-4,5-biphosphate. Binding of Ins(1,4,5)P3 to its receptor on the endoplasmic reticulum results in opening of the calcium channels and an increase in intracellular calcium. Ins(1,2)P2 (tested as the D L racemic mixture) is ~1,000-fold less potent than Ins(1,4,5)P3 at initiating Ca2+ release when injected into Xenopus oocytes.
D-myo-Inositol-1,3-phosphate (Ins(1,3)P) is a member of the inositol phosphate (InsP) molecular family that play critical roles as small, soluble second messengers in the transmission of cellular signals. The most studied InsP, Ins(1,4,5)P3 is a second messenger produced in cells by phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol-4,5-biphosphate. Binding of Ins(1,4,5)P3 to its receptor on the endoplasmic reticulum results in opening of the calcium channels and an increase in intracellular calcium. Ins(1,3)P2 can be dephosphorylated to Ins(1)P by inositol polyphosphate 3-phosphatase and further dephosphorylated to inositol by inositol monophosphatase.
Tenofovir diphosphate is an inhibitor of HIV reverse transcriptase (Kis = 0.022 and 1.55 μM for RNA and DNA, respectively) and hepatitis B virus (HBV) polymerase (Ki = 0.18 μM). It is selective for these enzymes over DNA polymerase α and β, as well as mitochondrial DNA polymerase γ (Kis = 5.2, 81.7, and 59.5 μM, respectively). Tenofovir diphosphate is formed intracellularly through phosphorylation of the prodrugs tenofovir and tenofovir disoproxil by nucleotide kinases. Increased levels of tenofovir diphosphate in isolated peripheral blood mononuclear cells (PBMCs) correlate with a decrease in the risk of simian HIV (SHIV) acquisition in a macaque model of rectal SHIV transmission.
Tenofovir diphosphate (TFV-DP) is a competitive inhibitor of DNA polymerases, specifically targeting dATP, and it serves as a substrate for the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1)[1].
Cabergoline diphosphate is a dopamine D2 receptor agonist used for prolactinoma treatment. Cabergoline permits rapid and effective hormonal and tumor control by normalizing prolactin-producing pituitary adenomas levels.